The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against viral variants

Efi Makdasi; Anat Zvi; Ron Alcalay; Tal Noy-Porat; Eldar Peretz; Adva Mechaly; Yinon Levy; Eyal Epstein; Theodor Chitlaru; Ariel Tennenhouse; Moshe Aftalion; David Gur; Nir Paran; Hadas Tamir; Oren Zimhony; Shay Weiss; Michal Mandelboim; Ella Mendelson; Neta Zuckerman; Ital Nemet; Limor Kliker; Shmuel Yitzhaki; Shmuel C. Shapira; Tomer Israely; Sarel J. Fleishman; Ohad Mazor; Ronit Rosenfeld

doi:10.1016/j.celrep.2021.109679

The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against viral variants

Efi Makdasi, Anat Zvi, Ron Alcalay, Tal Noy-Porat, Eldar Peretz, Adva Mechaly, Yinon Levy, Eyal Epstein, Theodor Chitlaru, Ariel Tennenhouse, Moshe Aftalion, David Gur, Nir Paran, Hadas Tamir, Oren Zimhony, Shay Weiss, Michal Mandelboim, Ella Mendelson, Neta Zuckerman, Ital NemetLimor Kliker, Shmuel Yitzhaki, Shmuel C. Shapira, Tomer Israely, Sarel J. Fleishman, Ohad Mazor, Ronit Rosenfeld

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Abstract

A wide range of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing monoclonal antibodies (mAbs) have been reported, most of which target the spike glycoprotein. Therapeutic implementation of these antibodies has been challenged by emerging SARS-CoV-2 variants harboring mutated spike versions. Consequently, re-assessment of previously identified mAbs is of high priority. Four previously selected mAbs targeting non-overlapping epitopes are now evaluated for binding potency to mutated RBD versions, reported to mediate escape from antibody neutralization. In vitro neutralization potencies of these mAbs, and two NTD-specific mAbs, are evaluated against two frequent SARS-CoV-2 variants of concern, the B.1.1.7 Alpha and the B.1.351 Beta. Furthermore, we demonstrate therapeutic potential of three selected mAbs by treatment of K18-human angiotensin-converting enzyme 2 (hACE2) transgenic mice 2 days post-infection with each virus variant. Thus, despite the accumulation of spike mutations, the highly potent MD65 and BL6 mAbs retain their ability to bind the prevalent viral mutants, effectively protecting against B.1.1.7 and B.1.351 variants.

Original language	English
Article number	109679
Journal	Cell Reports
Volume	36
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2021.109679
State	Published - 7 Sep 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

Funding

We thank Prof. Dr. Christian Drosten at the Charité Universitätsmedizin, Institute of Virology, Berlin, Germany, for providing the SARS-CoV-2 BavPat1/2020 strain. We wish to express our gratitude to our colleagues Dr. Sharon Melamed, Boaz Politi, Dr. Liat Bar-On, Yfat Yahalom-Ronen, and Dr. Emanuelle Mamroud for fruitful discussions and support. The graphical abstract was created with BioRender.com . Research in the Fleishman lab was supported by the Weizmann Institute CoronaVirus Fund and by a charitable donation in memory of Sam Switzer. We thank Prof. Dr. Christian Drosten at the Charit? Universit?tsmedizin, Institute of Virology, Berlin, Germany, for providing the SARS-CoV-2 BavPat1/2020 strain. We wish to express our gratitude to our colleagues Dr. Sharon Melamed, Boaz Politi, Dr. Liat Bar-On, Yfat Yahalom-Ronen, and Dr. Emanuelle Mamroud for fruitful discussions and support. The graphical abstract was created with BioRender.com. Research in the Fleishman lab was supported by the Weizmann Institute CoronaVirus Fund and by a charitable donation in memory of Sam Switzer. E.M. A.Z. R.A. T.N.-P. E.P. A.M. Y.L. E.E. A.T. M.A. D.G. S.J.F. O.M. and R.R. designed, carried out, and analyzed the data. M.M. E.M. N.Z. I.N. and L.K. isolated, sequenced, and provided the SARS-CoV-2 variant strains. N.P. H.T. and T.I. cultured and prepared SARS-CoV-2 viruses for the neutralization experiments. O.Z. and S.W. provided crucial reagents. S.Y. and S.C.S. added fruitful discussions. R.R. O.M. A.Z. and T.C. wrote the manuscript. O.M. and R.R. supervised the project. All authors have reviewed and approved the final manuscript. Patent application for the described antibodies was filed by the Israel Institute for Biological Research. None of the authors declared any additional competing interests.

Funders	Funder number
Institute of Virology
Israel Institute for Biological Research
Weizmann Institute CoronaVirus Fund
Horizon 2020 Framework Programme	871029

Keywords

K18-hACE2 mice
SARS-CoV-2
VOCs
escape mutants
mAbs
neutralizing antibodies
variants

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10.1016/j.celrep.2021.109679

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Makdasi, E., Zvi, A., Alcalay, R., Noy-Porat, T., Peretz, E., Mechaly, A., Levy, Y., Epstein, E., Chitlaru, T., Tennenhouse, A., Aftalion, M., Gur, D., Paran, N., Tamir, H., Zimhony, O., Weiss, S., Mandelboim, M., Mendelson, E., Zuckerman, N., ... Rosenfeld, R. (2021). The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against viral variants. Cell Reports, 36(10), Article 109679. https://doi.org/10.1016/j.celrep.2021.109679

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abstract = "A wide range of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing monoclonal antibodies (mAbs) have been reported, most of which target the spike glycoprotein. Therapeutic implementation of these antibodies has been challenged by emerging SARS-CoV-2 variants harboring mutated spike versions. Consequently, re-assessment of previously identified mAbs is of high priority. Four previously selected mAbs targeting non-overlapping epitopes are now evaluated for binding potency to mutated RBD versions, reported to mediate escape from antibody neutralization. In vitro neutralization potencies of these mAbs, and two NTD-specific mAbs, are evaluated against two frequent SARS-CoV-2 variants of concern, the B.1.1.7 Alpha and the B.1.351 Beta. Furthermore, we demonstrate therapeutic potential of three selected mAbs by treatment of K18-human angiotensin-converting enzyme 2 (hACE2) transgenic mice 2 days post-infection with each virus variant. Thus, despite the accumulation of spike mutations, the highly potent MD65 and BL6 mAbs retain their ability to bind the prevalent viral mutants, effectively protecting against B.1.1.7 and B.1.351 variants.",

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Makdasi, E, Zvi, A, Alcalay, R, Noy-Porat, T, Peretz, E, Mechaly, A, Levy, Y, Epstein, E, Chitlaru, T, Tennenhouse, A, Aftalion, M, Gur, D, Paran, N, Tamir, H, Zimhony, O, Weiss, S, Mandelboim, M, Mendelson, E, Zuckerman, N, Nemet, I, Kliker, L, Yitzhaki, S, Shapira, SC, Israely, T, Fleishman, SJ, Mazor, O & Rosenfeld, R 2021, 'The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against viral variants', Cell Reports, vol. 36, no. 10, 109679. https://doi.org/10.1016/j.celrep.2021.109679

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AU - Makdasi, Efi

AU - Zvi, Anat

AU - Alcalay, Ron

AU - Noy-Porat, Tal

AU - Peretz, Eldar

AU - Mechaly, Adva

AU - Levy, Yinon

AU - Epstein, Eyal

AU - Chitlaru, Theodor

AU - Tennenhouse, Ariel

AU - Aftalion, Moshe

AU - Gur, David

AU - Paran, Nir

AU - Tamir, Hadas

AU - Zimhony, Oren

AU - Weiss, Shay

AU - Mandelboim, Michal

AU - Mendelson, Ella

AU - Zuckerman, Neta

AU - Nemet, Ital

AU - Kliker, Limor

AU - Yitzhaki, Shmuel

AU - Shapira, Shmuel C.

AU - Israely, Tomer

AU - Fleishman, Sarel J.

AU - Mazor, Ohad

AU - Rosenfeld, Ronit

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KW - escape mutants

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The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against viral variants

Abstract

Bibliographical note

Funding

Keywords

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